A growing body of evidence indicates that chronic cocaine administration can
produce profound and long-lasting changes in brain neurochemical and
neuroendocrine systems. At the behavioral level, evidence is accumulating that
chronic use of cocaine compromises the neural mechanisms that mediate positive
reinforcement. This is illustrated, for example, by findings that cocaine
acutely facilitates the rewarding effects of intracranial self-stimulation,
while withdrawal after chronic use leads to an impairment in the rewarding
efficacy of electrical brain stimulation (Markou and Koob 1991). Findings such
as these have given rise to the view that compulsive drug-seeking behavior
associated with cocaine (and other drugs of abuse) may be the result of adaptive
processes within the central nervous system that oppose the acute reinforcing
actions of drugs, leading both to a "blunting" of mechanisms that mediate
positive reinforcement and the emergence of affective changes during withdrawal
that may motivate continued use of the drug (for example, anxiety, dysphoria,
and depression) during withdrawal (Koob and Bloom 1988; Koob et al. 1993; Wise
1996).

The following discussion reviews both earlier and recent studies that have
sought to identify the brain neurochemical processes responsible for the
compromised state of the reward system after chronic cocaine abuse and the
significance of those processes in the transition from controlled drug use to
compulsive drug-taking.

Neuroadaptive Changes Within Brain Reward Circuitries

Intravenous self-administration in rodents has been used successfully to
study cocaine-reinforced behavior. This methodology has significantly advanced
the understanding of the neurobiological basis of cocaine reinforcement and has
established a critical role for the mesoaccumbens dopamine (DA) systems in
cocaine's acute reinforcing effects. More recently, studies employing
intracranial microdialysis measures of DA in the nucleus accumbens (NAc) of
cocaine self-administering rats have confirmed the significance of DA in cocaine
reward and extended our understanding of interactions among cocaine, DA, and
other transmitters in this brain region in the regulation of cocaine-seeking
behavior.

When given the opportunity, both human cocaine abusers and laboratory animals
will often self-administer cocaine in sustained episodes that can last from
several hours to days. In humans, in particular, this so-called binge pattern of
cocaine abuse is associated with severe abstinence syndrome. In animals,
termination of access to cocaine after long-term unrestricted intravenous
self-administration produces behavioral disruptions and reward deficits believed
to be indicative of dependence and withdrawal (Markou and Koob 1991). Therefore,
this model was employed in conjunction with intracranial microdialysis to study
the neurochemical consequences of long-term cocaine self-administration and
cocaine withdrawal.

Dopamine.

Cocaine self-administration produced persistent elevations in extracellular
DA concentrations in the NAc that remained stable throughout 12- to 24-hour
periods of drug availability. Withdrawal from cocaine resulted in a marked
suppression of DA release below basal levels prior to self-administration (Weiss
et al. 1992b). Maximal inhibition of DA efflux was reached within 2 to 4
hours postcocaine, and the depression in extracellular DA levels did not recover
within a 12-hour monitoring period. The degree of suppression of DA release was
positively correlated with the number of hours of continuous cocaine
self-administration before withdrawal. Interestingly, as shown in earlier work,
deficits in brain stimulation reward also increased as a function of the
duration of continuous self-administration prior to withdrawal and were
reversible by administration of bromocriptine (Markou and Koob 1991, 1992; Weiss
et al. 1995). These data implicate a link between the withdrawal-associated
impairment in mesolimbic DA neurotransmission and behavioral abstinence symptoms
as measured by attenuated brain stimulation reward. However, it is important to
note that brain stimulation reward deficits are already evident shortly after
termination of access to cocaine, at a time when there is still some residual
elevation, rather than a deficit, in accumbal extracellular DA levels. This
observation supports the hypothesis that sustained dopaminergic stimulation by
long-term cocaine self-administration leads to adaptation of brain mechanisms
that mediate positive reinforcement.

Serotonin.

Cocaine self-administration not only increases extracellular DA levels in the
NAc but also produces similar elevations in extracellular serotonin (5-HT).
Given the established role of 5-HT in depression, a prominent cocaine withdrawal
symptom, it was of interest to determine whether cocaine withdrawal exerts
disruptive effects on 5-HT neurotransmission.

Withdrawal after 12 hours of unrestricted access to cocaine produced a
substantial suppression of 5-HT release in the NAc. Compared with basal 5-HT
levels in cocaine-naive controls, 5-HT efflux as measured by quantitative
microdialysis methods decreased by more than 50 percent as early as 6 hours
postcocaine (Parsons et al. 1995). In contrast to the serotonergic deficits
after long-term cocaine self-administration, only a trend toward suppression of
basal 5-HT release was apparent in rats after 24 hours of abstinence from daily
3-hour limited-access self-administration. These findings are consistent with
several reports in the literature of supersensitivity of 5-HT1a autoreceptors
and increased density of 5-HT uptake sites after intermittent cocaine
administration, but they also suggest that marked extracellular consequences of
these presynaptic changes become evident only after prolonged periods of
continuous cocaine self-administration. Decreased serotonergic transmission has
been implicated in symptoms of numerous psychiatric disorders such as
depression, panic disorder, insomnia, impulsiveness, and aggression-symptoms
also associated with cocaine abstinence. Therefore, the deficit in extracellular
5-HT concentrations may contribute directly to many aspects of the cocaine
withdrawal syndrome.

In addition to suppressing the release of 5-HT, withdrawal after long-term
access to intravenous cocaine altered the sensitivity of 5-HT1b receptors.
Locomotor activation in response to a 5-HT1b agonist (RU 24969) was diminished
during the first 2 days of cocaine withdrawal, while a persistent rebound
supersensitivity to 5-HT1b receptor activation emerged 1 week after cocaine
withdrawal. The initial subsensitivity is likely to reflect an adaptive
"downregulation" of 5-HT1b receptors that develops during long-term cocaine
self-administration to compensate for the sustained cocaine-induced increases in
synaptic 5-HT levels. Conversely, the subsequent supersensitivity is presumably
the result of sustained extracellular 5-HT deficiency during cocaine withdrawal.
These findings implicate 5-HT1b receptors, both in the cocaine withdrawal
syndrome and in locomotor sensitization produced by repeated cocaine
administration.

Recent studies have implicated the 5-HT1b receptor in the acute reinforcing
actions of cocaine. The 5-HT1b agonists produced a dose-dependent shift to the
left in the dose-effect function for self-administered cocaine and elevated
breaking points for cocaine on a progressive ratio schedule (Parsons et al.,
submitted). The enhancement of cocaine reward by 5-HT1b receptor activation
appeared to result from an augmentation in the accumulation of extracellular DA
in the NAc induced by cocaine, a finding that suggests that 5-HT1b receptors,
via stimulation by endogenous 5-HT, may have a role in cocaine reinforcement.
The subsensitivity of 5-HT1b receptors during the early withdrawal phase is,
therefore, interesting, not only with regard to its role in cocaine withdrawal
but also with regard to the general hypothesis that dependence may result from
adaptation of central reward mechanisms.

Changes In Brain Stress Systems After Chronic Cocaine

Recently, much attention has been directed at understanding the role of the
nonneuroendocrine corticotropin-releasing factor (CRF) system in the central
nucleus of the amygdala (CeA) in the affective consequences of stress and in
withdrawal from drugs of abuse. The CeA is part of a complex neural circuitry
regulating behavioral and autonomic responsiveness to stressful stimuli. In
particular, CRF neurons in the CeA are thought to have an essential role in the
mediation of emotional responses to stress, such as anxiety. Anxiety and
stress-like symptoms are an integral part of drug withdrawal syndromes, raising
the possibility that these withdrawal signs may involve activation of CRF
neuronal mechanisms in the CeA.

Initial findings indicated that acute intraperitoneal injections of cocaine
increase CRF release in the CeA of rats. This effect was significantly enhanced
by 2 weeks of daily cocaine pretreatment, implicating CRF mechanisms in the CeA
in cocaine sensitization as well as in the cross-sensitization between stress
and psychostimulants (Richter et al. 1995). In contrast to the effects of
noncontingent, intermittent cocaine administration, however, CRF release in the
CeA was significantly suppressed by cocaine in self-administering rats as
measured after completion of 2 weeks of cocaine self-administration training.
Moreover, in these animals, cocaine withdrawal after 12 hours of continuous
access to the drug produced a profound increase in CRF release, which reached
peak levels of approximately 400 percent of baseline between 11 and 12 hours
postcocaine (Richter and Weiss, submitted).

These data provide support for involvement of CRF mechanisms in the CeA in
the motivational effects of cocaine. Central administration of CRF has
stress-like anxiogenic and activational consequences in rats that can be
effectively reversed by treatments that interfere with CRF transmission in the
CeA. The effects of exogenous CRF resemble the behavioral signs of cocaine
withdrawal in animals; these effects may be comparable to human withdrawal
symptoms such as anxiety, agitation, irritability, restlessness, and confusion.
Thus, the activation of CRF release in the CeA during withdrawal may provide a
neurochemical basis for aspects of the cocaine abstinence syndrome. In contrast,
the suppression of CRF release by cocaine during the self-administration stage
may implicate attenuation of CRF release in the CeA as an element in the
reinforcing actions of cocaine. Finally, these data extend previous observations
on the activation of CRF mechanisms in the CeA during opiate, ethanol, and
cannabinoid withdrawal and implicate enhanced amygdaloid CRF release as a common
mechanism in symptoms of anxiety and negative affect that are typically
associated with drug withdrawal syndromes (de Fonseca et al. 1997; Merlo Pich et
al. 1995).

The evidence of a hyperactivity within an important brain stress regulatory
center during cocaine withdrawal is intriguing in view of the established role
of stress in drug abuse and dependence. Stress is a major determinant of relapse
in humans and can increase the intake of psychostimulant drugs; it can also
facilitate the acquisition of psychostimulant self-administration in laboratory
animals. While many stress-associated drug-seeking behaviors may involve
activation of the hypothalamic CRF system and the hypothalamic-pituitary-adrenal
axis, the present data support an essential role for amygdalar CRF neurons in
drug-seeking behavior motivated by stress or anxiety effects related to cocaine
abstinence.

Studies examining the interaction between stress and psychostimulant
withdrawal indicate that, in addition to disturbances in the brain CRF system,
chronic psychostimulant exposure can disrupt normal stress responses at other
levels. For example, not only did termination of daily amphetamine treatment
result in a long-lasting deficit in extracellular DA concentrations in the NAc,
but also stimulation of DA release in response to restraint stress, which is a
typical response to this stressor in drug-naive animals, was no longer observed
during amphetamine withdrawal. In fact, restraint stress produced a persistent
reduction in extracellular DA concentration below basal levels that were already
lowered by withdrawal from chronic amphetamine (Weiss et al., in press). Thus,
certain forms of stress may exacerbate the neurochemical consequences of
psychostimulant withdrawal by further lowering extracellular DA levels and,
thereby, perhaps contribute to the resumption of drug-seeking behavior and
increased likelihood of relapse associated with stress. Moreover, the reversal
of the dopaminergic response to immobilization stress was not confined to acute
abstinence but was still observed at the same magnitude 7 days postamphetamine.
This persistent suppression in DA release after stress may reflect a disruption
of mechanisms that regulate affective homeostasis, leading to an impairment in
the ability to cope with stress or emotional challenges. Such defects may have
important implications for emotional states such as depression or helplessness
and for vulnerability to relapse over a prolonged abstinence period.

Chronic Cocaine And Behavioral Plasticity

The data discussed above identify perturbations in brain reward and
stress systems as an important element in neuroadaptive changes induced by
chronic cocaine. Another important factor associated with chronic use of cocaine
(and other drugs of abuse) may involve plasticity within brain circuitries that
mediate conditioning effects or stimulus-response associations. Indeed, the
classical conditioning of cocaine's pharmacological effects with specific
drug-associated environmental stimuli is an important aspect of its behavioral
actions. Cocaine-associated stimuli can mimic the drug's locomotor-activating
effects and control place preference induced by repeated pairing of cocaine
injections with a specific environment. The conditioning of cocaine's rewarding
actions with environmental stimuli has important implications for its abuse
potential. Clinical observations suggest that stimuli previously associated with
availability or self-administration of the drug can evoke intense subjective
feelings of craving and can trigger episodes of relapse in abstinent cocaine
abuse patients.

Experimental studies of drug-seeking behavior associated with drug-related
stimuli in rats indicate that incentive motivational stimuli associated with
cocaine can elicit and maintain robust cocaine-seeking behavior in the absence
of drug availability. For example, rats responding for presentation of
conditioned stimuli previously paired with food or cocaine showed a strong shift
in preference for a cocaine- over a food-associated stimulus after receiving a
noncontingent "priming" injection of cocaine. This effect was particularly
sensitive to reversal by a dopamine D1 antagonist, implicating activation of D1
receptors in the motivational effects of cocaine under these conditions.

In rats trained to self-administer cocaine intravenously, presentation of a
discriminative stimulus previously predictive of cocaine availability elicited
significant and persistent responding after extended periods of abstinence and
increased DA efflux in the NAc. The reinstatement of cocaine-seeking behavior
was blocked by both dopamine D1 and D2 antagonists. Together, these observations
implicate activation of dopaminergic mechanisms in the motivational effects of
drug-associated environmental stimuli and drug-priming. Moreover, these data
suggest that cocaine-related cues may exert a "priming" action since, like
cocaine, these stimuli increase extracellular levels of DA in the NAc.

Summary

It has been proposed that drug addiction is the result of neuroadaptive
processes within the central nervous system that oppose the acute reinforcing
actions of drugs of abuse (Koob and Bloom 1988), leading to impairment in the
mechanisms that mediate positive reinforcement and the emergence of affective
changes such as anxiety, dysphoria, and depression during withdrawal. The
results reveal perturbations in DA and 5-HT transmission in the
NAc-neurochemical systems that are activated by cocaine self-administration and
are deficient during withdrawal-as potential substrates for these affective
changes. In addition, the results implicate neuroadaptive changes in
extrahypothalamic CRF neurons and other brain stress circuitries in the
motivational effects of psychostimulant withdrawal. Finally, it appears that
environmental cues that become conditioned to the positive reinforcing effects
of cocaine can mimic the pharmacological effect of this agent and, thereby, can
initiate and maintain cocaine-seeking behavior.

Acknowledgment

This research was supported by National Institute on Drug Abuse Grant No.
DA-07348.